Abstract
The development of in vivo biomarkers of Alzheimer’s disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease, which is characterized by core neuropathological features of amyloid plaques and neurofibrillary tangles that result in synaptic loss, neurodegeneration, and cognitive and behavioural manifestations [1]
The definition of AD has been shifted from a clinical syndrome to a biological construct as proposed in the 2018 National Institute on Aging— Alzheimer’s Association (NIA-AA) Research Framework, where a combination of syndromal cognitive staging and biomarker profiles (A+T−(N)−: Alzheimer’s pathologic change; A+T+(N) − and A+T+(N)+: Alzheimer’s disease; A+T−(N)+: Alzheimer’s and concomitant suspected non-Alzheimer’s pathologic change) forms the biological Alzheimer’s continuum [5]
Articles were included if they met the following 5 criteria: 1) The study population consisted of participants who: (i) met the criteria for preclinical AD as defined by the NIA-AA Research Framework [5], or (ii) were cognitively unimpaired without preclinical AD – defined participants who scored within normal limits on baseline cognitive testing or neuropsychological assessment or had a Clinical Dementia Rating (CDR) score of 0
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease, which is characterized by core neuropathological features of amyloid plaques and neurofibrillary tangles that result in synaptic loss, neurodegeneration, and cognitive and behavioural manifestations [1]. The identification of AD biomarkers in the AT(N) classification scheme that cross the pathological threshold in cognitively unimpaired individuals has led to the conceptual framework of a preclinical stage in the AD continuum [6, 7] This concept is further validated in presymptomatic autosomal dominant AD mutation-carriers where in vivo pathophysiological markers are elevated years prior to the onset of symptoms [8]. It has been postulated that the pathophysiology of AD has a pattern of temporal evolution, starting with Aβ plaques and fibrillar tau, followed by neuronal dysfunction as the eventual pathway, leading to cognitive impairment [12, 13] This hypothesis has been supported by a study in preclinical AD which showed that Aβ and hyperphosphorylated tau aggregates synergistically interact to cause a downstream metabolic decline in brain networks affected early in AD [14]. Given that neuropsychiatric symptoms (NPS) may be the first manifestation of AD rather than cognition in nature, further studies are needed to evaluate where NPS fit in the AT(N) pathophysiological pathway
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